Significance

This study shows that neurodegenerative changes induced by α-synuclein in midbrain dopamine neurons in vivo can be blocked through activation of the autophagy-lysosome pathway. Using an adeno-associated virus model of Parkinson disease to overexpress α-synuclein in the substantia nigra, we show that genetic [transcription factor EB (TFEB) and Beclin-1 overexpression] or pharmacological (rapalog) manipulations that enhance autophagy protect nigral neurons from α-synuclein toxicity, but inhibiting autophagy exacerbates α-synuclein toxicity. The results provide a mechanistic link between α-synuclein toxicity and impaired TFEB function, and identify TFEB as a target for therapies aimed at neuroprotection and disease modification in Parkinson disease.

Abstract

The aggregation of α-synuclein plays a major role in Parkinson disease (PD) pathogenesis. Recent evidence suggests that defects in the autophagy-mediated clearance of α-synuclein contribute to the progressive loss of nigral dopamine neurons. Using an in vivo model of α-synuclein toxicity, we show that the PD-like neurodegenerative changes induced by excess cellular levels of α-synuclein in nigral dopamine neurons are closely linked to a progressive decline in markers of lysosome function, accompanied by cytoplasmic retention of transcription factor EB (TFEB), a major transcriptional regulator of the autophagy-lysosome pathway. The changes in lysosomal function, observed in the rat model as well as in human PD midbrain, were reversed by overexpression of TFEB, which afforded robust neuroprotection via the clearance of α-synuclein oligomers, and were aggravated by microRNA-128–mediated repression of TFEB in both A9 and A10 dopamine neurons. Delayed activation of TFEB function through inhibition of mammalian target of rapamycin blocked α-synuclein induced neurodegeneration and further disease progression. The results provide a mechanistic link between α-synuclein toxicity and impaired TFEB function, and highlight TFEB as a key player in the induction of α-synuclein–induced toxicity and PD pathogenesis, thus identifying TFEB as a promising target for therapies aimed at neuroprotection and disease modification in PD.

Footnotes

↵1To whom correspondence may be addressed. E-mail: Mickael.Decressac{at}med.lu.se or anders.bjorklund{at}med.lu.se.

Author contributions: M.D. and A.B. designed research; M.D., B.M., P.W., and M.L. performed research; J.J. contributed new reagents/analytic tools; M.D. and A.B. analyzed data; M.D. and A.B. wrote the paper; P.W. performed the HPLC analyses; M.L. performed the amperometry measurements and analyzed these data; and J.J. designed the microRNA vector.

Sign up for Article Alerts

Jump to section

You May Also be Interested in

For too long, the considerable importance and impacts of recreational fisheries have been ignored. Policymakers and managers need to do a better job acknowledging and addressing this very influential sector.

Fossil evidence helps address a longstanding debate on the evolution of hagfish, a jawless, marine-dwelling slime “eel,” and suggests that living jawless vertebrates may not be as primitive as their anatomy suggests.